The goal of this project is to complete a novel asymmetric formal synthesis of the marine natural product (+)- neopeltolide, utilizing the Petasis-Ferrier union/rearrangement strategy as a macrocyclic ring closure. (+)- Neopeltolide has risen to the attention ofthe chemical community as a natural product with significant anti- proliferation activity against three important cancer cell lines, with IC50's of 1.2, 5.1, and 0.56 nM against A- 549 human lung adenocarcinoma, the NCI-ADR-RES human ovarian sarcoma, and the P388 murine leukemia cell lines, respectively. The key transformation in this synthesis is the first usage ofthe Petasis- Ferrier union/rearrangement as a macrocyclic closure reaction sequence. Successful implementation ofthe macrocyclic closure would comprise a significant extension of the utility of the Petasis-Ferrier tactic. Assuming the successful completion of (+)-neopeltolide in the next six months, I will then commence the total synthesis ofthe natural product, englerin A. This highly cytotoxic compound was isolated from the East African plant Phyllanthus engleri and demonstrated GI50 values between 1-87 nM against six different renal cancer cell lines. The key step in this synthetic sequence, an enantioselective intermolecular [4C+3C] cycloaddition, will advance the knowledge ofthe chemical community and the understanding ofthis powerful transformation. According to the most recent review published by Newman in the Journal of Natural Products (J. Nat. Prod. 2007, 70, 461) about 50% of newly discovered molecules with biological activity, or "new chemical entities," are natural products or directly derived from natural products. Development of new routes to synthesize natural products and natural product derivatives, while simultaneously expanding the methodology ofthe Petasis-Ferrier union/rearrangement, is fundamental to the process of drug discovery.